Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that primarily affects the synovial joints. RA can also produce diffuse inflammation in the lungs and pleura as well as form subcutaneous nodular lesions. About 1-2% of the world's population is affected by RA and there is a gender bias associated with disease onset; women are three-times more likely to develop RA than men between the ages of 35 and 50.
Inflammation as the primary driver of pathology had previously been restricted to infectious diseases and autoimmune disorders; however, it is become more apparent that inflammation plays a larger role in multiple disease states such as obesity, coronary artery disease and cancer. While the precise cause of RA remains unclear, a greater understanding of the underlying mechanisms of the disease has facilitated the development of a number of therapies that target the mediators of inflammation. For example, such therapies include biologics, most notably, antibodies that capture or neutralize disease-driving cytokines.
It is well documented that JAK kinases play a pivotal role in cytokine receptor signaling to phosphorylate and activate signal transducer and activator of transcription (STAT) proteins. Several of these JAK-controlled cytokine receptor pathways are intimately involved in the initiation and progression of RA disease pathogenesis. Cytokines involved in chronic inflammatory processes (e.g., IL-2, IL-6, IL-12, IFNγ, and GM-CSF) are also essential to a proper functioning immune response to infectious agents. JAK2 is involved in the downstream activation of STAT3 and STAT5 and is responsible for transducing signals for several proinflammatory cytokines involved in the pathogenesis of RA including IL-6, IFNγ and IL-12. Other molecules implicated in the pathogenesis of RA include BLyS/BAFF, APRIL, p38/MAPK and the BCR protein tyrosine kinase, Syk.
Approved treatments for RA include NSAIDs, anti-metabolites such as methotrexate and leflunomide, various corticosteroids and glucocorticoids, sulfasalazine, and various biologics including abatacept (Orencia®), adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), and rituximab (Rituxan®). The recent FDA approval of tocilizumab (anti-IL-6R) (Actemra®) further demonstrates the power of targeting cytokines and associated receptors to treat chronic inflammatory diseases.
However, biologics present several disadvantages over orally active small molecules, such as the cost of production, the need for multiple injections, and the possibility for anaphylactic reactions. Small molecules are thought to provide another, perhaps complimentary, approach to treating inflammation by targeting cytokine pathways via the inhibition of key kinases involved in transducing cytokine receptor signals. Oral bioavailability is another reason that small molecules are an attractive method to treat disease.
Therapeutic control of chronic inflammation is essential for the clinical management of many highly prevalent disease states including RA. Accordingly, the development of safe and effective treatments for these debilitating conditions remains an important medical need.